We previously showed that monocyte-derived macrophages (MDM) infected with HIV-1 produce high levels of macrophage colony stimulating factor (M-CSF). M-CSF production paralleled both the rate and amount of HIV-1 produced and enhanced production of M-CSF was dependent on active replication of HIV-1. This was supported by our finding that treatment of HIV- infected MDM with AZT leads to complete inhibition of HIV-1 RT activity, and also ablates the production of M-CSF. The lymphokine, interleukin-2 (IL-2), reportedly upregulates M-CSF receptor expression and enhances M-CSF production by human monocytes, which increase the susceptibility of MDM to HIV-1 infection. IL-2 has been successfully used for therapeutic restoration of CD4+ T cells in AIDS patients, but its use is accompanied by a transient burst of HIV-1 RNA from unidentified cells. We investigated the ability of IL-2 to enhance HIV-1 expression in MDM by upregulating M-CSF production. Intriguingly, we found that exposure of MDM to IL-2 prior to infection leads to a dramatic decrease in HIV-1 replication, which correlates with an IL-2-induced down-modulation of the HIV-1 receptors CD4, CCR5 and CCR3. However, M-CSF production was not modulated (AIDS Fast Track 1998, 12:F59-F64).[unreadable]Other studies looking at the effects of interleukin 15 (IL-15), which has similar biological activities and shares a common receptor gamma chain, show that IL-15 has no effect on HIV-1 replication when added prior to infection, but inhibits replication when added post infection. IL-15 does not modulate HIV receptor expression and it can stimulate production of M-CSF, suggesting that IL-2 and IL-15 have unique effects on MDM. Our results could lead to new therapeutic approaches directed at eliminating expression of HIV in human MDM, thereby reducing the possibility of transmission of virus to the more susceptible CD4+ T lymphocytes. Although M-CSF can modulate the susceptibility and rate of infection of MDM with HIV-1 and its production is enhanced following infection, its role in the infection of MDM with other viruses has not been characterized. We infected MDM with a panel of single stranded RNA viruses including HIV-1, HIV-2, measles virus (MV) and respiratory syncitial virus (RSV). We found that infection of MDM with monocytropic strains of HIV-2 also leads to enhanced production of M-CSF. However, infection of MDM with MV or RSV does not induce endogenous production of M-CSF. Specific production of M-CSF in response to HIV infection provides an example of how the virus uses a host derived protein to promote its survival and suggests that M-CSF antagonists may play an important role in the treatment of HIV disease.